Weekly gemcitabine plus Epirubicin as effective chemotherapy for advanced pancreatic cancer: a multicenter phase II study

The current role of chemotherapy in pancreatic carcinoma is limited, and progress in the treatment of this disease represents a significant challenge to medical oncology. The most promising drug under study is gemcitabine, a relatively new antimetabolite that represents an attractive candidate for combination chemotherapy because of its excellent side-effect profile and the absence of overlapping toxicities with other chemotherapeutic agents. Combined administration of gemcitabine and anthracyclines could result in the induction of DNA breaks that are not easily repaired by the cell's machinery, thus enhancing the apoptotic signals triggered by these lesions. Forty-four patients with locally advanced and/or metastatic pancreatic adenocarcinoma were enrolled in this multicenter study. Patients received Epirubicin 20 mg m−2 for 3 weeks followed by 1 week of rest (1 cycle) and gemcitabine 1000 mg m−2 after Epirubicin on the same day. All were assessable for toxicity and response, 11 patients responded to treatment with one complete response and 10 partial responses, for an overall response rate of 25%. Median survival was 10.9 months (range, 2–26 months). Therapy was well tolerated, with a low incidence of haematologic grade >2 toxicity. A total of 12 of 27 (44.4%) eligible patients attained a clinical benefit response. Our findings suggest that the gemcitabine-epirubicin schedule is active and well tolerated in patients with advanced pancreatic cancer

Physical activity levels are positively related to progression-free survival and reduced adverse events in advanced ER+ breast cancer

Background Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case–control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. Methods In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n  = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into “active” and “insufficiently active” to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. Results Compared to “insufficiently active” patients, “active” individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p  = .0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be “active” at baseline revealed significantly fewer AEs compared to “insufficiently” active patients. In detail, both severe and non-severe AEs occurred less frequently in the “active” patients group. In line with that, QoL and fatigue were better in physical “active” patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. Conclusions Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients’ QoL and fatigue. Trial registration EUPAS9462. Registered 30th October 2012 “retrospectively registered.”Open Access funding enabled and organized by Projekt DEAL.Technische Universität Dortmund (1006

HER-2/neu diagnostics in breast cancer

HER-2/neu status of the primary breast cancer (PBC) is determined by immunohistochemistry and fluorescent in situ hybridization. Because of a variety of technical factors, however, the PBC may not accurately reflect the metastatic tumor in terms of HER-2/neu status. Recently published guidelines recommend that tumors be defined as HER-2/neu positive if 30% or more of the cells are 3+. Circulating levels of the HER-2 extracellular domain can be measured in serum using a test cleared by the US Food and Drug Administration, and increased serum HER-2/neu levels to above 15 ng/ml can reflect tumor progression. Studies comparing tissue HER-2/neu status of the PBC and HER-2/neu levels above 15 ng/ml in metastatic breast cancer patients are also reviewed

Association between breast cancer and estrogen receptor gene polymorphism PVU II

643 Background: The estrogen receptor (ER) is well acknowledged as a prognostic factor in breast cancer, and it is a prerequisite to use the predictive information for hormonal therapy. We investigated whether that the different polymorphisms of the estrogen receptor could influence its expression or functionality. Methods: DNA was extracted from white blood cells of 236 breast cancer patients and 236 healthy, matched controls. The ER genotypes were determined by polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion of the PCR product. Results were shown by electrophoreses. Clinical data such as histologic types, pTNM stage and patients age were available for statistical analyses. Results: We found a statistically significant correlation between the estrogen receptor polymorphism pattern and breast cancer. The receptor type PP was detected statistically significantly more often in postmenopausal breast cancer patients (PP vs pp+Pp, p =0.03). However, there was no correlation to the histobiochemical receptor status or UICC-Stadium. Conclusions: These results show an association between the estrogen receptor polymorphism and breast cancer. It seems to be that a complete lack of the p-allel is a risk factor to develop breast cancer at postmenopausal age. There was no influence on estrogen receptor expression or clinical tumor stage. Thus, we propose that there is no clinical use for estrogen receptor polymorphism analyses at this stage. No significant financial relationships to disclose. </jats:p

Tissue inhibitor of metalloproteinases 1 (TIMP-1) and tumor type M2 pyruvate kinase (TuM2-PK) were compared with established markers in advanced colorectal cancer

13537 Background: Recently, a high expression of TIMP-1 was demonstrated by immunohistochemistry in colorectal cancer (CRC). TIMP-1 can also be detected in plasma of those patients (pts). We investigated the longitudinal concentrations of TIMP-1 in 37 pts with advanced CRC and correlated the monitoring performance of TIMP-1 to CEA and CA 19–9 as established markers of tumor load in CRC. In addition, the plasma level of TuM2-PK as novel marker of disease activity was integrated into the analysis. Methods: Plasma TIMP-1 (Bayer Diagnostics/Oncogene Science, Tarrytown/Boston, USA) and TuM2-PK (Schebo Biotech, Giessen, Germany) levels were measured using standardized ELISA assays while serum CEA and CA 19–9 were determined using chemiluminescence immunoassays (Bayer Diagnostics, Tarrytown/NY). The nonparametric analysis of variance for repeated measurements by Brunner was used to test for time effects between the selected 3 time points: 1. baseline at initiation of systemic chemotherapy for metastatic disease; 2: best response; 3: later progression. Results: We grouped 37 pts with regard to best response to chemotherapy as follows: complete or partial remission (CR/PR): n=10; stable disease (SD): n=21; primary progressive disease (PD): n=6. TIMP-1 and TuM2-PK concentrations increased significantly from baseline to progression (p&lt;0.001 and p=0.003, respectively). The plasma levels of patients with objective response (CR/PR) dropped significantly for TuM2-PK (p=0.001) and TIMP-1 (p=0.001), while CA 19–9 and CEA did not change (p=0.94 and p=0.10, respectively). No significant change could be demonstrated in the SD group for TuM2-PK (p=0.26), TIMP-1 (p=0.69) and for CEA (p=0.25), whereas CA 19–9 concentrations decreased significantly (p=0.04). Conclusions: Innovative markers like TIMP-1 and TuM2-PK provided a much higher monitoring quality than established markers like CEA and CA 19–9 in advanced CRC. As the later cancer-associated proteins are recommended by internationally acknowledged guidelines, larger comparative trials are warranted asking the important question whether a replacement of CEA by one or a panel of new markers may provide additional clinical information. No significant financial relationships to disclose. </jats:p

Evaluation of CUB-Domain-Containing Protein (CDCP1)-Expression as Predictive Marker of Adhesion-Independant Cell Survival in Breast Cancer Cell Lines.

Abstract Background: A crucial step in the metastatic cascade is to overcome anoikis, a type of programmed cell death after loss of cell-cell contact. CDCP1 has recently been indentified to be an essential prerequisite for anoikis resistance in lung adenocarcinoma cell lines [Uekita et al. 2007]. CDCP1 is overexpressed in distinct tumor tissues and suspected to signal via Src family kinases (SFK). Since CDCP1 overexpression has been detected in a variety of primary breast cancers and cell lines [Bühring et al. 2004], this study aimed at investigating the correlation between CDCP1 expression and anoikis-resistance in breast cancer cell lines and the involvement of SFKs.Material and Methods: Various breast cancer cell lines were tested for their CDCP1 status by FACS analysis and immunoblotting. CDCP1-negative breast cancer cell line MCF7 and primary normal breast cells were compared to the CDCP1-high cell lines MDA-MB-231 (∼90% positive cells (p.c.)), T47D (∼65% p.c.), SKBR3 (∼52% p.c.) and HBL100 (∼60% p.c.) when cultured in ultra low-adhesion culture plates. Apoptosis rate was evaluated measuring the nucleosome enrichment factor (EF). SFK-involvement was tested via proliferation analysis after treatment with SKF-inhibitor PP2 and its inactive derivate PP3. Since various types of breast cancer were influenced by the presence or absence of steroids, MDA-MB-231 cells and HBL100 cells were stimulated with ß17-Estradiol and CDCP1 expression was measured using relative quantification in qRT-PCR.Results: When grown in solution on ultra-low adhesion plates, CDCP1-negative primary normal breast cells underwent apoptosis (EF:5,29). CDCP1-high expressing MDA-MB-231 cells (EF:1,75) were less apoptotic than T47D (EF:3,68:) and SKBR3 cells (EF:4,35). However, CDCP1-negative MCF7 breast cancer cells were relatively resistant towards loss of anchorage (EF:2,03). When grown in suspension, proliferation rate of MDA-MB-231 is 6-fold lower than in normal tissue plates, both cultured with or without SFK-inhibitor PP2. Proliferation rate of CDCP1-negative MCF7 cells grown in solution in presence and absence of PP2 is even 24-fold reduced. MDA-MB-231 cells show a significant 50% reduction in RNA-levels of CDCP1 when cultured 48h in presence of ß17-ER (10-8M). However, in HBL100 cells, no change of RNA-level of CDCP1 was detectable.Conclusions: Anoikis resistance seems to directly correlate with the expression level of CDCP1, when cells are cultured in suspension. However, CDCP1-negative cell line MCF7 also shows relative resistance towards loss of anchorage. Thus, anoikis resistance may not be a monocausal phenomenon. Nonetheless, high level of CDCP1-expression also promotes cell proliferation in absence of anchorage to an extracellular matrix. RNAi-mediated knock-down will elucidate if CDCP1 is also involved in cell migration or invasion. Our studies show, that CDCP1-expression level has strong impact on the capacity of breast cancer cell lines to grow and survive anchorage independent - an essential prerequisite for metastatic potential. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6167.</jats:p